Project Summary The goal of this project is to generate data and reagents that help uncover critical functions of the poorly characterized members of ion channels. We prioritize mouse models, given the high value investigators place on phenotypes observed for genetic perturbation. However, we focus on co-perturbation of ion channel genes and their interacting genetic components as opposed to singly altering ion channel genes in mouse models. This approach will validate our proteomics approaches in the most definitive manner- in vivo. We see in vivo exploration as an essential step to evaluate ion channel function. Our major aims include mapping ion channel interactions and complexes using a high-throughput proteomics platform at UCSF. These data will be interrogated using integrative approaches established by the Monarch Initiative, where biochemical interactions will be validated and prioritized for further study. Another major aim is function-centric: we use mouse models to elucidation of human disease mechanisms, where we embrace a genetic interaction scheme to uncover ion channel redundancy and polygenic effects. Together these integrative approaches complement each other, specifically the in vivo genetic interaction platform interrogates those genes identified from proteomics and bioinformatics analysis. We generate critical reagents and data including antibodies and gene expression patterns. Our broad goal is to identify ion channel phenotypes relevant to fundamental human disease. We bring on board a number of ion channel experts and mouse phenotyping specialists who can accomplish this major programs goals in an efficient manner.